Epidermal growth factor receptors (EGFRs) are highly expressed in many human cancers. Four EGFRs have been reported: EGFR, HER2, HER3, and HER4. Three of these, EGFR, HER2, and HER3, have been implicated in cancers, especially in aggressive lung, breast, and ovarian cancers.
EGFRs belong to the transmembrane receptor tyrosine kinase family of receptors that mediate cell signaling and influence cell growth, differentiation, and motility. These receptors are activated by ligands that change the conformation of the extracellular domains. Ligand binding induces receptor dimerization and activation of intracellular tyrosine kinase activity, which in turn leads to downstream signaling pathways. In normal cells, following activation of the initial signal transduction mechanism, receptor activation is attenuated by mechanisms such as receptor internalization and down-regulation. However, aberrant EGFR signaling occurs in certain cancers. Signal dysregulations due to receptor mutation, constitutive activation, overexpression of receptors, and dimerization have been reported in several types of cancers.
Non-small-cell lung cancer is the most common type of lung cancer. It is a leading cause of cancer deaths worldwide. In approximately 18-33% of non-small-cell lung cancer tumors human epidermal growth factor receptor-2 (HER2) is overexpressed. The prognosis of patients with lung cancer is poor, with a typical survival rate around one year. The coexpression of EGFR and HER2 is associated with an even lower survival rate. HER2 is also overexpressed in 20-30% of invasive breast cancers. HER2:HER3 dimers, and the interaction of HER2 with HER3 and EGFR are known to be important in HER2-overexpressing breast tumors.
Existing approaches to cancer therapy include chemotherapeutic agents, hormonal therapy, antibodies targeted to the HER2 protein, and tyrosine kinase inhibitors. Amplification of the HER2 gene is associated with poor prognosis and resistance to certain chemotherapeutic agents. Hormonal therapy is not an option for HER2-positive cancers. Antibodies and tyrosine kinase inhibitors have shown some positive responses in treating such types of cancers. However, there are limitations to the stability and immunogenicity of antibodies. There are more than 500 different kinases in the body that can be affected by tyrosine kinase inhibitors. Resistance to tyrosine kinase inhibitors typically develops within a few years.
Satyanarayanajois S, Villalba S, Jianchao L, Lin G M. (2009). Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines. Chem. Biol. Drug Des. 74: 246-257 discloses the in silico screening of several peptidomimetics for their effect on HER2 binding.
To treat HER2-positive cancers such as breast cancer, the HER2 domain IV has been targeted by an antibody such as trastuzumab, and HER2 domain II has been targeted by an antibody such as pertuzumab. See A. Badache and N. Hynes, A new therapeutic antibody masks ErbB2 to its partners, Cancer Cell, April 2004, 299-301; and Biobusiness Briefs, ERBB2 dimerization inhibitor meets end point in breast cancer trial, Nature Drug Discovery, vol. 10, September 2011, 648.
Peptides targeting HER2 are disclosed in A. Berezov et al., Disabling ErbB Receptors with Rationally Designed Exocyclic Mimetics of Antibodies: Structure-Function Analysis, J. Med. Chem. 2001, 44, 2565-2574; S. Pero et al., Identification of a small peptide that inhibits the phosphorylation of ErbB2 and proliferation of ErbB2 overexpressing breast cancer cells, Int. J. Cancer: 111, 951-960 (2004); A Berezov et al., Disabling ErbB receptors with rationally designed exocyclic mimetics of antibodies: structure-function analysis, J. Med. Chem. 2001, 44, 2565-2574; and N. Dakappagari et al., Conformation HER-2/neu B-cell epitope peptide vaccine designed to incorporate two native disulfide bonds enhances tumor cell bonds enhances tumor cell binding and antitumor activities, J. Biol. Chem.: 280, 54-63 (2005).
R. Fasan et al, Structure-activity studies in a family of β-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction, ChemBioChem, 2006, 7, 515-526 discloses the use of a cyclic peptide incorporating D-Pro and L-Pro to target HDM2-p53 protein interactions.
H. Cho et al., Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab, Nature, 2003, 421, 756-760 describes studies with the antibody trastuzumab suggesting that HER2 is a potential target for anticancer therapies.
S. Banappagari et al., A conformationally constrained peptidomimetic binds to the extracellular region of HER2 protein, J. Biomol. Struc.: 28, No. 3, 1-20 (2010) discloses several peptidomimetics designed to inhibit HER2-mediated heterodimerization and signaling. See also S. Banappagari et al., Structure-activity relationship of conformationally constrained peptidomimetics for antiproliferative activity in HER2-overexpressing breast cancer cell lines, Med. Chem. Commun., 2011, 2: 752-759.
Banappagari S, Corti M, Pincus S, Satyanarayanajois S D. (2012). Inhibition of protein-protein interaction of HER2-EGFR and HER2-HER3 by a rationally designed peptidomimetic. J. Biomol. Struct. Dyn. 30: 594-606 discloses a peptidomimetic that bound specifically to the HER2 protein extracellular domain and disrupted the dimerization of EGFRs. See also Banappagari, S., McCall, A., Fontenot, K., Vicente, M. G. H., Gujar, A., Satyanarayanajois, S. D. (2013). Design, synthesis and characterization of peptidomimetic conjugate of BODIPY targeting HER2 protein extracellular domain. Eur J. Med. Chem. 65C: 60-69.
There is an unfilled need for improved treatments for patients with HER2-overexpressed cancers such as lung, breast, and ovarian cancers.